Common variable immune deficiency (CVID) is the clinically most important primary antibody deficiency disease due to prevalence, complications, hospitalizations and requirement for lifelong immune globulin therapy. B cells of patients lack the capacity for normal somatic hyper-mutation and isotype switch, secrete immune globulins poorly, and fail to differentiate into plasma cells. The genetic causes of B cell dysfunction in CVID are largely unknown. Heterozygous mutations in the transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) gene are found in 8-10%, but also in relatives with normal immune globulin levels showing that these are not the main cause of severe B cell dysfunction. However, CVID subjects with TACI mutation especially in heterozygous form are significantly more likely to develop striking lymphoid hyperplasia and autoimmunity. Using human B cells and transfectants with TACI mutations, we will investigate TACI receptor function in humans, examining if monoallellic or biallelic mutations in TACI accelerate BAFF/BAFF-R mediated B cell growth ahd differentiation. TLR agonists with TACI signals may promote self-reactivity as well as play a role in B cell differentiation in humans, thus we will examine how these may drive B cell proliferation and autoimmunity in CVID, especially when TACI signals are impaired. As human B cells have two structurally different TACI isoforms we will determine the differences in functional capacities, and explore the controls on the production of these naturally occurring isoforms. A current hypothesis is that mutations in TACI could lead to haploinsufficiency;we will investigate this by examining B cell function in patients with the Smith Magenis syndrome, who are heterozygous for a null TACI allele due to a chromosomal deletion. In this project we hypothesize that mutations in TACI found in subjects with CVID and their non immune deficient relatives, can be used to explore how the TACI receptor and its ligands, BAFF and APRIL, control B cell growth and differentiation in humans. These data may be of use in understanding this complex receptor system in human autoimmune disease in general.